PROJECT SUMMARY In this project, we aim to study the role of chemosensory detection in inflammatory diseases of the nose and sinuses. These diseases?in particular rhinitis and rhinosinusitis?are extremely prevalent and bothersome disorders. Recently, basic science research in rodents has demonstrated a contribution to airway mucosal immunity from taste signaling pathways in specialized cells known as solitary chemosensory cells (SCCs). We have recently discovered these cells in human tissues, and our long-term objective is to examine the role of SCCs in human sinonasal health and disease. Our first aim is to use immunolocalization techniques on human tissues to determine where these cells are located in the sinonasal cavity, and infer their possible roles. We expect to see a moderate abundance of this cell type, and uneven distribution, based on our prior experiments. Understanding the distribution of SCCs in the airway will inform future research using tissue biopsies. In the second aim, we will examine the distribution of taste receptors based on anatomic location and disease state. There are 25 human bitter taste receptors, and we expect to see that some of these are found more often in the front of the nose, whereas others will be found deeper in the sinuses. Similarly, some may be more expressed in disease states such as allergic rhinitis and chronic rhinosinusitis. To test this hypothesis, we will evaluate the relative expression of these bitter taste receptors in different areas of the airway, and compare healthy to diseased patient tissues. Then, we will test putative natural ligands for bitter receptors using calcium imaging in a heterologous expression system. These findings will establish the connection of chemosensory detection to the human diseases of rhinitis and rhinosinusitis, and open the door for novel therapies to treat these highly burdensome chronic diseases. In the third and final aim, we will evaluate if taste transduction is required to regulate the bacterial colonization of the mucosal surface. The microbiome varies markedly between people, yet the host factors that influence bacterial colonization are poorly understood. Prior evidence in rodents and humans has shown that SCCs and bitter taste mechanisms are able to detect respiratory pathogens and initiate a response to kill and clear these bacteria. In this aim, we will use modern DNA sequencing techniques to examine the airway surface bacterial communities from (1) mice that lack the ability to use bitter taste pathways, and (2) humans that have a genetic bitter receptor defect (T2R38). We will also use novel gene-targeting approaches to interrogate second messenger pathways and immune processes activated by SCCs.